Site-specific or targeted delivery of drugs is considered a valuable tool to improve the therapeutic efficacy and to reduce the toxicity of drugs. For example, antibody-drug-conjugates are known in the art and may, for example, consist of a recombinant antibody covalently bound to a small therapeutic compound (typically 300 to 1,000 Da) via a synthetic linker (S. C. Alley et al., Curr. Opin. Chem. Biol. 2010, 14:529-537).
Whereas non-targeted drug compounds or diagnostic compounds typically reach their intended target cells via whole-body distribution and passive diffusion or receptor mediated uptake over the cell membrane, targeted drugs or targeted diagnostic compounds home-in and concentrate mainly at the targeted tissues. Consequently, targeted drugs (herein meant as drugs targeted by a targeting moiety) or diagnostic compounds require smaller dosages while still allowing the drug to reach therapeutically or diagnostically effective levels inside or at the level of the target lesion or cells and thus improving the therapeutic or diagnostic window.
In this regard it is important to note that in general it is favorable if the amounts of targeted therapeutic compounds that reach the target cells can be adjusted according to their efficacy, in other words that the accumulation of therapeutic compounds at the target cell needs to be higher in case they are less potent (e.g., less cytotoxic). For diagnostic compounds, a high accumulation at the target cell is generally considered advantageous, unless this reduces the signal as, e.g., in case of quenching.
The use of targeted diagnostic compounds is of great value for whole body imaging and can be used for patient selection and response prediction for targeted therapeutics (personalized medicine) and for validation of therapeutic responses to targeted therapeutic compounds.
The targeting of therapeutic compounds or diagnostic compounds to specific cells is thus a conceptually attractive method to enhance specificity, to decrease systemic toxicity compared to conventional delivery and to allow for the therapeutic or in-vivo diagnostic use of compounds that are in principle less suitable or unsuitable as systemic drugs. Drug targeting is achieved when an alteration in the drug's bio-distribution favors drug accumulation at the desired site, which site is usually remote from the administration site. Cell-selective delivery of therapeutic agents (drugs) can, in principle, be obtained by coupling drug molecules to targeting moieties which targeting moieties are a member of a specific binding pair, i.e., a member from a pair of molecules wherein one of the pair of molecules has an area on its surface or a cavity which specifically binds to, and is, therefore, defined as complementary with, a particular spatial and polar organization of the other molecule, so that the pair have the property of binding specifically to each other. Examples of types of specific binding pairs are antigen-antibody, biotin-avidin, hormone-hormone receptor, receptor-ligand, enzyme-substrate, IgG-protein A. Particularly suitable targeting moieties from such binding pairs are macromolecular carriers, such as, for example, monoclonal antibodies, antibody fragments or engineered variants thereof or low molecular weight carriers, such as, for example, peptides.
However, the linkage between the therapeutic compound and the targeting moieties often poses significant problems. For instance, the linking of lipophilic non-targeted therapeutic compounds to hydrophilic targeting moieties may be difficult,
Furthermore, chemically reactive groups for conventional conjugation chemistry may be absent, or chemically reactive groups may be (abundantly) present, but (covalent) linkage may (irreversibly) inhibit the bioactivity of the coupled therapeutic compound.
In International Patent Application WO 2013/103301 methods are described for linking therapeutic compounds to targeting moieties by using (transition) metal ion complexes as a linker between the therapeutic compounds and the targeting moieties. This way, cell targeting conjugates are prepared, which work well in-vivo.
However, analyses have shown that a fraction of the functional moiety and platinum linker may detach from the binding site on the targeting moiety. In a clinical setting this would result in the presence of free functional moieties, such as (super) toxic drugs and free platinum in the body. Hence, a need exists for cell targeting conjugates that are more stable, i.e., wherein the functional moieties do not detach from the binding site on the targeting moieties outside the intended place of action.